Compositions comprising tramadol and celecoxib in the treatment of pain

ABSTRACT

The present invention relates to pharmaceutical compositions comprising tramadol and celecoxib and their uses as medicaments or analgesics, more particularly for the treatment of severe to moderate pain with an inflammation component.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.13/394,995, filed Mar. 8, 2012, now allowed. U.S. patent applicationSer. No. 13/394,995 is a U.S. National Phase filing under 35 U.S.C. §371of International Application PCT/EP2010/006317, filed Oct. 15, 2010, andpublished as WO 2011/045075 on Apr. 21, 2011. PCT/EP2010/006317 claimedbenefit of priority from European Patent Application No. EP 09384004.9,filed Oct. 16, 2009. The entire contents of each of the priorapplications are incorporated herein by reference.

The present invention relates to pharmaceutical compositions comprisingtramadol and celecoxib and their uses as medicaments or analgesics, moreparticularly for the treatment of severe to moderate pain.

Pain is a complex response that has been functionally categorized intosensory, autonomic, motor, and affective components. The sensory aspectincludes information about stimulus location and intensity while theadaptive component may be considered to be the activation of endogenouspain modulation and motor planning for escape responses. The affectivecomponent appears to include evaluation of pain unpleasantness andstimulus threat as well as negative emotions triggered by memory andcontext of the painful stimulus.

In general, pain conditions can be divided into chronic and acute.Chronic pain includes neuropathic pain and chronic inflammatory pain,for example arthritis, or pain of unknown origin, as fibromyalgia. Acutepain usually follows non-neural tissue injury, for example tissue damagefrom surgery or inflammation, or migraine. Pain may also be divided intodifferent levels of severity starting from severe through moderate tolight pain.

There are many drugs that are known to be useful in the treatment ormanagement of pain. Opioids are frequently used as analgesics in pain.Derivatives of morphine are indicated for the treatment of moderate toacute pain in human. The analgesic effect is obtained through theiraction on morphinic receptors, preferably the p-receptors. Among thesederivatives of morphine, morphine, codeine, pethidine,dextropropoxyphenemethadone, lenefopan may be mentioned.

One of the morphinic derivatives that has shown very good results whenorally administrated, and which is extensively marketed, is tramadol,also available as a physiologically acceptable salt, particularly as achlorohydrate. Tramadol is a central acting analgesic drug that exertsits effects by activating opioid receptors and enhancing neuronalmonoamine synaptic concentration. Tramadol, whose chemical name is2-(dimethylaminomethyl)-1-(3-methoxyphenyl)cyclohexanol, has thefollowing formula:

This structure shows two different chiral centers and thus the moleculemay exist in different diastereoisomers among which the tramadol is thecis-diastereoisomer. The enantiomers (1R,2R), or (1S,2S), are also knownas (+)-tramadol and (−)-tramadol with both of them contributing indifferent ways to the overall activity of racemic tramadol.

“(rac)” is according to this invention defined as the abbreviation of“racemate” and thus “(rac)-tramadol” or “(rac)tramadol” means racemictramadol (the cis-diastereoisomer) as described in the paragraph above.

Accordingly, “(rac)-tramadol.HCl” or “(rac)tramadol.HCl” is defined asthe hydrochloride salt of racemic tramadol (the cis-diastereoisomer) asdescribed above.

From the art it appears that this compound is neither fully opioid-like,nor non-opioid-like. Some studies have demonstrate that tramadol is anopioid agonist, whereas clinical experience indicates that it lacks manyof the typical side effects of opioids agonist, for example respiratorydepression, constipation or tolerance.

Due to their drawbacks, opioids used as analgesics to treat pain cannotalways be given repeatedly or at higher doses. The effects of opioidsare reviewed for example by J. Jaffe in “Goodman and Gilman's, ThePharmacological Basis of Therapeutics”, 8th edition; Gilman et al.;Pergamon Press, New York, 1990, Chapter 22, pages 522-573.

Consequently it has been proposed to combine opioids with other drugsthat are not opioid analgesic agents, in order to lower the amount ofopioids needed to produce an equivalent degree of analgesia. Among thesecombinations, the association of tramadol with nonsteroidalanti-inflammatory drugs (NSAIDs) has been reported to be of particularinterest (EP-0 546 676).

U.S. Pat. No. 5,516,803 discloses combination of tramadol withnon-steroidal anti-inflammatory drugs (NSAIDs), specifically ibuprofenand discloses the combination of tramadol.HCl with non-steroidalanti-inflammatories, such as for example ibuprofen, in a compositionratio of 1:1 to 1:200 producing a synergistically enhanced analgesicaction and reducing the undesired accompanying symptoms

U.S. Pat. No. 6,558,701 patent discloses combination of tramadol withdiclofenac and “for the treatment of moderate to severe pain, the WorldHealth Organization (WHO) recommends combining opioid analgesics withnon-steroidal analgesics in order to produce a more effective painrelief and possibly reduce amounts of analgesic which are necessary toadminister”.

One interesting NSAIDs to be combined with tramadol is the marketed drugcelecoxib, whose chemical name is4-[5-(4-methylphenyl)-3-(trifluoromethyl)-pyrazol-1-yl]-benzenesulfonamide.Celecoxib is an anti-inflammatory and pain killer drug and it is one ofthe most used treatments for chronic musculo-skeletal inflammatoryillnesses. It has an empirical formula of C₁₇H₁₄F₃N₃O₂S.

Celecoxib is an oral, highly selective cyclooxygenase-2 (COX-2)inhibitor, and it is indicated for the treatment of symptomatic reliefin the treatment of osteoarthritis, rheumatoid arthritis and ankylosingspondylitis (Goldenberg M M. Celecoxib, a selective cyclooxygenase-2inhibitor for the treatment of rheumatoid arthritis and osteoarthritis.Clin. Ther. 1999, 21, 1497-513). This high selectivity allows celecoxiband other COX-2 inhibitors to reduce inflammation (and pain) whileminimizing gastrointestinal adverse drug reactions (e.g. stomach ulcers)that are common with non-selective NSAIDs.

Cyclooxygenase is responsible for generation of prostaglandins. Twoisoforms, COX-1 and COX-2, have been identified. COX-2 is the isoform ofthe enzyme that has been shown to be induced by pro-inflammatory stimuliand has been postulated to be primarily responsible for the synthesis ofprostanoid mediators of pain, inflammation, and fever. COX-2 is alsoinvolved in ovulation, implantation and closure of the ductusarteriosus, regulation of renal function, and central nervous systemfunctions (fever induction, pain perception and cognitive function). Itmay also play a role in ulcer healing. COX-2 has been identified intissue around gastric ulcers in man but its relevance to ulcer healinghas not been established.

WO00/51685 describes pharmaceutical composition comprising on one hand atramadol material selected from:

-   -   (+)- and (−)-tramadol, racemic tramadol, the N-oxide of tramadol        and O-desmethyl-tramadol (both of them as isolated stereoisomers        or mixtures thereof including their racemates) either as free        base or as a salt, solvate or polymorph;        and on the other hand a selective COX-2 inhibitor with celecoxib        being listed among the COX-2 inhibitor drugs. The focus of the        application rests in the exemplified combination of tramadol and        JT-522.

The applicant has now found that tramadol, especially the (rac)-tramadolhydrochloride salt, having the opioid activity, and celecoxib(especially in its neutral form) can be combined in one pharmaceuticalcomposition achieving an additive effect, especially in the treatment ofsevere to moderate pain, especially in pain with an inflammatoryelement.

Thus the object of the present invention is a pharmaceutical compositioncomprising a combination of (rac)tramadol.HCl and celecoxib or apharmaceutically acceptable salt or hydrate thereof.

In general each separate active principle of the pharmaceuticalcomposition according to the invention, the tramadol and the celecoxib,has its own disadvantages when used alone.

Thus, tramadol hydrochloride, which is often used orally, displays ahighly bitter taste, which makes the drugs often difficult to swallowand lowers patient compliance. Also, as stated before, the drawbacksassociated with opioids—their side effects—are limiting their use, sothat they have to be given at lower doses and often less frequent astheir use as analgesics to treat pain would normally require. On theother hand celecoxib is well-known to be only slightly soluble in waterand this is further limiting its use in pharmaceutical formulations.

The object of the present invention is to provide a pharmaceuticalcomposition comprising an opioid like tramadol and an NSAID likecelecoxib having a level of efficacy similar to the one achievable byeach active substance used alone, but:

-   -   with a better safety profile at higher doses and/or    -   —by showing a synergistic effect—allowing a reduction of dose        while still delivering the desired activity using less of each        ingredient and, therefore, reducing the side effects associated        with each active principle; and/or    -   providing a new more effective method for treating acute or        severe to moderate pain, especially in pain with an inflammatory        component.

Other desirable improvements/advantages of the new pharmaceuticalcomposition would include being active in diseases or symptoms being orrelated to pain and its subtypes, especially those in which currenttreatment is insufficient like sciatica or frozen shoulder or painrelated to central sensitization (central pain syndrome).

Most desirably the pharmaceutical composition should combine more thanone, most preferably all of these advantages.

This pharmaceutical composition according to the invention showsimproved properties if compared to any of the active principles alone.

In one preferred embodiment of the pharmaceutical composition accordingto the invention the celecoxib is in neutral form.

As celecoxib is weakly acidic with a pKa of 11.1 its “neutral form”according to the invention is defined therefore as the form in whichcelecoxib is free (not in form of a salt) but is—depending on thepH—neutral or carrying a load.

In one further embodiment of the pharmaceutical composition according tothe invention the ratio of the (rac)-tramadol.HCl to the celecoxib is aweight ratio of from about 1:1 to about 1:300 or from about 1:1 to about300:1.

In one further embodiment of the pharmaceutical composition according tothe invention the ratio of the (rac)-tramadol.HCl to the celecoxib is amolar ratio of from about 1:1 to about 1:300 or from about 1:1 to about300:1.

In one further embodiment of the pharmaceutical composition according tothe invention the molecular ratio of the (rac)-tramadol.HCl to thecelecoxib is a weight ratio of from about 1:1 to about 1:30 or fromabout 1:1 to about 30:1.

In one further embodiment of the pharmaceutical composition according tothe invention the molecular ratio of the (rac)-tramadol.HCl to thecelecoxib is a molar ratio of from about 1:1 to about 1:30 or from about1:1 to about 30:1.

In one further embodiment of the pharmaceutical composition according tothe invention the molecular ratio of the (rac)-tramadol.HCl to thecelecoxib is a molar ratio of from about 1:1 to about 1:5 or from about1:1 to about 5:1.

Another advantage is that the association of the two active principlesinto one unique species seems to allow for a betterPharmacokinetic/Pharmacodynamic (PKPD) including also a betterpenetration of the blood-brain barrier, which helps in the treatment ofpain.

Both parts of the pharmaceutical composition are well-known drugs usedfor a long time worldwide. Due to the therapeutic interest in tramadolin the treatment of pain symptoms and the well-known properties ofcelecoxib in this field of medical indication, a further object of thepresent invention is a medicament containing a pharmaceuticalcomposition comprising (rac)-tramadol.HCl and celecoxib.

Thus, the invention also relates to a medicament containing apharmaceutical composition comprising (rac)-tramadol.HCl and celecoxibaccording to the invention as described above and optionally one or morepharmaceutically acceptable excipients.

The medicament or pharmaceutical composition according to the presentinvention may be in any form suitable for the application to humansand/or animals, preferably humans including infants, children and adultsand can be produced by standard procedures known to those skilled in theart. The medicament can be produced by standard procedures known tothose skilled in the art, e.g. from the table of contents of“Pharmaceutics: The Science of Dosage Forms”, Second Edition, Aulton, M.E. (ED. Churchill Livingstone, Edinburgh (2002); “Encyclopedia ofPharmaceutical Technology”, Second Edition, Swarbrick, J. and Boylan J.C. (Eds.), Marcel Dekker, Inc. New York (2002); “Modern Pharmaceutics”,Fourth Edition, Banker G. S. and Rhodes C. T. (Eds.) Marcel Dekker, Inc.New York 2002 y “The Theory and Practice of Industrial Pharmacy”,Lachman L., Lieberman H. And Kanig J. (Eds.), Lea & Febiger,Philadelphia (1986). The respective descriptions are hereby incorporatedby reference and form part of the disclosure. The composition of themedicament may vary depending on the route of administration.

The medicament or pharmaceutical composition of the present inventionmay for example be administered parentally in combination withconventional injectable liquid carriers, such as water or suitablealcohols. Conventional pharmaceutical excipients for injection, such asstabilizing agents, solubilizing agents, and buffers, may be included insuch injectable compositions. These medicaments or pharmaceuticalcompositions may for example be injected intramuscularly,intraperitoneally, or intravenously.

Medicaments or pharmaceutical compositions according to the presentinvention may also be formulated into orally administrable compositionscontaining one or more physiologically compatible carriers orexcipients, in solid or liquid form. These compositions may containconventional ingredients such as binding agents, fillers, lubricants,and acceptable wetting agents. The compositions may take any convenientform, such as tablets, pellets, granules, capsules, lozenges, aqueous oroily solutions, suspensions, emulsions, or dry powdered forms suitablefor reconstitution with water or other suitable liquid medium beforeuse, for immediate or controlled release. The multiparticulate forms,such as pellets or granules, may e.g. be filled into a capsule,compressed into tablets or suspended in a suitable liquid.

Suitable controlled release formulations, materials and methods fortheir preparation are known from the prior art, e.g. from the table ofcontents of “Modified-Release Drug Delivery Technology”, Rathbone, M. J.Hadgraft, J. and Roberts, M. S. (Eds.), Marcel Dekker, Inc., New York(2002); “Handbook of Pharmaceutical Controlled Release Technology”,Wise, D. L. (Ed.), Marcel Dekker, Inc. New York, (2000); “ControlledDrug Delivery”, Vol, I, Basic Concepts, Bruck, S. D. (Ed.), CRD PressInc., Boca Raton (1983) y de Takada, K. and Yoshikawa, H., “Oral DrugDelivery”, Encyclopedia of Controlled Drug Delivery, Mathiowitz, E.(Ed.), John Wiley & Sons, Inc., New York (1999), Vol. 2, 728-742; Fix,J., “Oral drug delivery, small intestine and colon”, Encyclopedia ofControlled Drug Delivery, Mathiowitz, E. (Ed.), John Wiley & Sons, Inc.,New York (1999), Vol. 2, 698-728. The respective descriptions are herebyincorporated by reference and form part of the disclosure.

Medicaments or pharmaceutical compositions according to the presentinvention may also comprise an enteric coating, so that theirdissolution is dependent on pH-value. Due to said coating the medicamentmay pass the stomach undissolved and the respective pharmaceuticalcomposition and its components is/are liberated in the intestinal tract.Preferably the enteric coating is soluble at a pH value of 5 to 7.5.Suitable materials and methods for the preparation are known from theprior art.

Typically, the medicaments or pharmaceutical compositions according tothe present invention may contain 1-60% by weight of the combination of(rac)-tramadol.HCl and celecoxib as defined herein and 40-99% by weightof one or more auxiliary substances (additives/excipients).

The compositions of the present invention may also be administeredtopically or via a suppository.

The daily dosage for humans and animals may vary depending on factorsthat have their basis in the respective species or other factors, suchas age, sex, weight or degree of illness and so forth. The daily dosagefor humans preferably is in the range of 10 to 2000 milligrams of activesubstance to be administered during one or several intakes per day.

A further aspect of the invention relates to a pharmaceuticalcomposition according to the invention comprising the combination of(rac)-tramadol.HCl and celecoxib according to the invention for use asan analgesic for the treatment of pain, preferably acute pain, chronicpain, neuropathic pain, hyperalgesia, allodynia or cancer pain,including diabetic neuropathy and osteoarthritis; as well as severe tomoderate pain; including also rheumatoid arthritis, ankylosingspondylitis, sciatica and frozen shoulder. The use of the pharmaceuticalcomposition might especially be drawn to the treatment of severe tomoderate pain with an inflammatory component like e.g. rheumatoidarthritis, ankylosing spondylitis, sciatica and frozen shoulder.

A further aspect of the invention relates to a pharmaceuticalcomposition according to the invention comprising the combination of(rac)-tramadol.HCl and celecoxib according to the invention for use asan analgesic or for the treatment of pain, preferably acute pain,chronic pain (acute and chronic pain), neuropathic pain, nociceptivepain (visceral and/or somatic pain), mild and severe to moderate pain,hyperalgesia, pain related to central sensitization, allodynia or cancerpain, including diabetic neuropathy or diabetic peripheral neuropathyand osteoarthritis, fibromyalgia; rheumatoid arthritis, ankylosingspondylitis, frozen shoulder or sciatica. A further aspect of theinvention relates to a pharmaceutical composition according to theinvention comprising the combination of (rac)-tramadol.HCl and celecoxibaccording to the invention for the treatment of pain, preferably acutepain, or preferably acute pain, chronic pain (acute and chronic pain),neuropathic pain, nociceptive pain (visceral and/or somatic pain), mildand severe to moderate pain, hyperalgesia, pain related to centralsensitization, allodynia or cancer pain, including diabetic neuropathyor diabetic peripheral neuropathy and osteoarthritis, fibromyalgia;rheumatoid arthritis, ankylosing spondylitis, frozen shoulder orsciatica. The invention thus also relates to the use of a co-crystalaccording to the invention as described above in the production of amedicament for the treatment of pain, preferably acute pain, chronicpain (acute and chronic pain), neuropathic pain, nociceptive pain(visceral and/or somatic pain), mild and severe to moderate pain,hyperalgesia, pain related to central sensitization, allodynia or cancerpain, including diabetic neuropathy or diabetic peripheral neuropathyand osteoarthritis, fibromyalgia; rheumatoid arthritis, ankylosingspondylitis, frozen shoulder or sciatica.

A related further aspect of the invention is aimed at the use of apharmaceutical composition according to the invention as described abovein the manufacture of a medicament for the treatment of pain, preferablyacute pain, chronic pain, neuropathic pain, hyperalgesia, allodynia orcancer pain, including diabetic neuropathy, fibromyalgia orosteoarthritis; as well as severe to moderate pain; including alsorheumatoid arthritis, ankylosing spondylitis, sciatica and frozenshoulder. Preferably this use is provided for in form of a medicament ora pharmaceutical composition according to the invention as describedabove. This medicament might especially be drawn to the treatment ofsevere to moderate pain with an inflammatory component like e.g.rheumatoid arthritis, ankylosing spondylitis, sciatica and frozenshoulder. Another related further aspect of the invention is aimed atthe use of a pharmaceutical composition according to the invention asdescribed above in the manufacture of a medicament for the treatment ofpain, preferably acute pain, chronic pain (acute and chronic pain),neuropathic pain, nociceptive pain (visceral and/or somatic pain), mildand severe to moderate pain, hyperalgesia, pain related to centralsensitization, allodynia or cancer pain, including diabetic neuropathyor diabetic peripheral neuropathy and osteoarthritis, fibromyalgia;rheumatoid arthritis, ankylosing spondylitis, frozen shoulder orsciatica.

Another object of the current invention is a method of treatment ofpain, preferably acute pain, chronic pain, neuropathic pain,hyperalgesia, allodynia or cancer pain, including diabetic neuropathy,fibromyalgia or osteoarthritis; as well as severe to moderate pain;including also rheumatoid arthritis, ankylosing spondylitis, sciaticaand frozen shoulder, by providing to a patient in need thereof asufficient amount of the pharmaceutical composition comprising thecombination of (rac)-tramadol.HCl and celecoxib according to theinvention as described above. This method of treatment might especiallybe relevant for the treatment of severe to moderate pain with aninflammatory component like e.g. rheumatoid arthritis, ankylosingspondylitis, sciatica and frozen shoulder. Another related object of theinvention is aimed at a method of treatment of pain, preferably acutepain, chronic pain (acute and chronic pain), neuropathic pain,nociceptive pain (visceral and/or somatic pain), mild and severe tomoderate pain, hyperalgesia, pain related to central sensitization,allodynia or cancer pain, including diabetic neuropathy or diabeticperipheral neuropathy and osteoarthritis, fibromyalgia; rheumatoidarthritis, ankylosing spondylitis, frozen shoulder or sciatica byproviding to a patient in need thereof a sufficient amount of thepharmaceutical composition comprising the combination of(rac)-tramadol.HCl and celecoxib according to the invention as describedabove.

“Pain” is defined by the International Association for the Study of Pain(IASP) as “an unpleasant sensory and emotional experience associatedwith actual or potential tissue damage, or described in terms of suchdamage (IASP, Classification of chronic pain, 2^(nd) Edition, IASP Press(2002), 210). Even though pain is always subjective its causes orsyndromes can be classified. One classification to denominate subtypesof pain would be to divide the general pain syndrome into the subtypesof acute and chronic pain or—according to the pain intensity—into mild,moderate and severe pain. In other definitions the general pain syndromeis also divided into “nociceptive” (caused by activation ofnociceptors), “neuropathic” (caused by damage to or malfunction of thenervous system) and pain related to central sensitization (central painsyndrome).

“Sciatica” or “sciatic neuritis” is defined herein as a set of symptomsincluding pain that derive from irritation of the sciatic nerve or itsroots,

“Frozen shoulder” or “adhesive capsulitis” is defined herein as asymptom wherein the connective tissue surrounding the shoulder joint orthe shoulder capsule itself is causing chronic pain, becoming inflamedand stiff.

“Ankylosing spondylitis” or “Morbus Bechterew” is a chronic,inflammatory arthritis and autoimmune disease. It mainly affects jointsin the spine and the sacroilium in the pelvis, causing eventual fusionof the spine.

“Pain related to central sensitization”/“central pain syndrome” isdefined within this application as a neurological condition caused bydamage to or dysfunction of the central nervous system (CNS), whichincludes the brain, brainstem, and spinal cord. This syndrome can interalia be caused by stroke, multiple sclerosis, tumors, epilepsy, brain orspinal cord trauma, or Parkinson's disease.

“Nociceptive pain ” is defined as a type of pain caused by activation ofnociceptors. It can be divided into somatic and visceral pain. “Visceralpain” is pain generally originating from the organs, whereas “(deep)somatic pain” originates from ligaments, tendons, bones, blood vessels,fasciae and muscles.

BRIEF DESCRIPTION OF THE FIGURES:

FIG. 1:

A: Dose response curves of antihyperalgesic effects of tramadol,celecoxib and different combinations of racemic tramadol hydrochloridewith celecoxib at different ratios (1:1, 1:3 and 3:1) in the rat pawincision model of postoperative pain.

B: Isobologram analysis showing significant (p<0.01) synergisticinteraction on thermal hyperalgesia. All data are presented as means±SEM(n=10-13 per dose group).

The present invention is illustrated below with the help of thefollowing examples. These illustrations are given solely by way ofexample and do not limit the invention.

EXAMPLES Example 1 Preparation of Composition Doses of TramadolHydrochloride and Celecoxib

Combinations of a racemic tramadol hydrochloride and celecoxib wereprepared at different molar ratios of (rac)-tramadol.HCl:celecoxib (1:1,1:3 and 3:1). All drugs and combinations were dissolved in 0.5%hydroxypropyl methylcellulose in distilled water and administered in avolume of 10 ml/kg per rat through the intraperitoneal (i.p.) route. InTable 1 are listed the different ratios prepared at the variousconcentrations,

TABLE 1 Corresponding doses of each drug or combinations administeredintraperitoneally. Doses (mg/kg) Tramadol 2.5 10 40 Celecoxib 0.625 2.510 40 Ratio 1:1 0.3130 0.625 2.5 10 40 Ratio 1:3 2.5 10 40 Ratio 3:10.625 2.5 10 40

Effects on Thermal Hyperalgesia in a Postoperative Pain Model in Rat

The aim of this study was to evaluate the analgesic efficacy and potencyof compositions comprising a combination of tramadol/celecoxib,especially a combination of racemic tramadol hydrochloride withcelecoxib in different molar ratios (1:1, 1:3 and 3:1) in a rat model ofpostoperative pain after paw incision. To assess the reliability of theefficacy and potency of the compounds tested thermal hypersensitivity(hyperalgesia) was performed using the plantar test assay (Hargreaves etal., Pain 1988, 32, 77).

Experimental Design Animals

Male, Wistar rats (120-160 g, Harlan, Italy) were housed in aclimate-controlled room for at least 5 days prior to testing. Food andwater were available ad libitum up to test time.

Animal Dosing

The rats were all dosed intraperitoneally with compositions comprising acombination of racemic tramadol hydrochloride and celecoxib at differentratios, dissolved in a suspension of 0.5% hydroxypropyl methylcellulosein distilled water. The dosing volume was 10 ml/kg. The antihyperalgesicresponse of the animal was subsequently evaluated 60 min aftercompositions administration.

Surgery

Rats were anaesthetized with 3% isofluorane and a 1 cm longitudinalincision was made through skin and fascia of the plantar surface of thepaw, starting 0.5 cm from the proximal edge of the heel and extendingtoward the toes. Both superficial (skin) and deep (muscle) tissues andnerves were injured. Finally, the skin of the paw was stitched with asuturing stitch with breaded silk (3.0).

Assessment of Analgesic Activity in Post-Operative Pain in Rats

The drugs were tested 4 hours after the surgery (plantar incision); 60minutes after the administration of the product,

Assessment of Thermal Hypersensitivity (Hyperalgesia) in Post-OperativePain in Rats

Thermal hypersensitivity or hyperalgesia was assessed by measurement ofa response to a thermal stimulus using a Hargreaves apparatus (UgoBasile plantar test) which selectively elevates the temperature of anindividual paw (Dirig, et al., J Neurosci Methods, 1997, 76, 183).Animals were placed in the methacrylate cages of said apparatus, havinga crystal floor. The acclimation period within the cages was about 10minutes. The thermal stimulus came from a lamp moving below the crystalfloor and which was applied to both paws, with a minimum interval of 1minute between both stimulations in order to avoid learning behaviours.The rat is able to withdraw the paw freely when it feels discomfort(pain) produced by the heat coming from the lamp; then it is switchedoff and the latency time to the withdrawal response is recorded inseconds. In order to avoid hurting the animal's paw, the lamp wasautomatically switched off after 32 seconds. Hyperalgesia is defined asan increased response to a painful stimulus and the analgesic effect ofthe test compound is seen as a (partial) restoration of the latencytoward normal (Dirig, et al., J. Pharmacol Expt Therap. 1998, 285,1031).

Analysis of Synergistic Effect

The synergistic interaction between tramadol and celecoxib wasdetermined by isobologram analysis as discloses by R. J. Tallarida, etal., Life Sci., 1989, 45, 947. This procedure involves the determinationof the total amount in the mixture that is required to produce aspecified synergistic anti-hyperalgesic effect at the 50% dose level(that is, the ED₅₀ or Zt) and the corresponding total amount that wouldbe expected under simple additivity (ED₅₀ add or Zadd). Where it isestablished that Zt<Zadd for a specific fixed-ratio, then thatcomposition has a synergistic anti-hyperalgesic effect. Both ED₅₀ t andED₅₀ add values are random variables. ED₅₀ t is determined from thedose-response curve for a specific fixed-ratio of the components; ED₅₀add is calculated from the ED₅₀ values for the individual drugs. Zt isthen compared to Zadd via a Student's t-test.

Results

In this study, dose response curves of compositions comprising acombination of racemic tramadol hydrochloride and celecoxib at differentratios (1:1, 1:3 and 3:1) were obtained (see FIG. 1A). All drugs inducedfull efficacy when thermal hypersensitivity was evaluated.

All ratios of combination of racemic tramadol hydrochloride withcelecoxib resulted to act synergistically inhibiting thermalhyperalgesia in postoperative pain rats. The ratios 1:1 and 3:1 improvedsignificantly around 4 times the antihyperalgesic effects. The ratio 1:3improved around 1 time the antihyperalgesic effects (see Table 2 andFIG. 1B).

TABLE 2 Statistic comparative analysis of Zt (experimental) versus Zadd(additive) using a student's t-test. Combination ratio Zt Zadd Ratio 1:12.26 ± 0.48**  9.41 ± 1.49 4.16 3:1 1.81 ± 0.41** 7.97 ± 1.2 4.40 1:311.07 ± 1.25   13.59 ± 1.67 1.23

Conclusion

Compositions comprising a combination of racemic tramadol hydrochlorideand celecoxib show synergistic interaction to inhibit thermalhyperalgesia in the rat paw incision postoperative pain model.

1. A pharmaceutical composition comprising a synergistic combination of(rac)-tramadol.HCl and celecoxib or a pharmaceutically acceptable saltor hydrate thereof, wherein the molecular ratio of the(rac)-tramadol.HCl to the celecoxib is a molar ratio of from about 1:1to about 1:3 or from about 1:1 to about 3:1.
 2. A pharmaceuticalcomposition according to claim 1, wherein the molecular ratio of the(rac)-tramadol.HCl to the celecoxib is a molar ratio of about 3:1.
 3. Apharmaceutical composition according to claim 1, wherein the molecularratio of the (rac)-tramadol.HCl to the celecoxib is a molar ratio ofabout 1:3.
 4. A pharmaceutical composition according to claim 1, whereinthe molecular ratio of the (rac)-tramadol.HCl to the celecoxib is amolar ratio of about 1:1.
 5. A pharmaceutical composition according toclaim 1, wherein the celecoxib is in neutral form.
 6. A pharmaceuticalcomposition according to claim 1, wherein the composition is a liquidcomposition.
 7. A method for the treatment of pain comprisingadministering to a subject in need thereof a therapeutically effectiveamount of at least one pharmaceutical composition according to claim 1.8. A method according to claim 7, wherein said pain is selected fromacute pain, chronic pain, neuropathic pain, nociceptive pain, mild andsevere to moderate pain, hyperalgesia, pain related to centralsensitization, allodynia or cancer pain, diabetic neuropathy, diabeticperipheral neuropathy, osteoarthritis, fibromyalgia, rheumatoidarthritis, ankylosing spondylitis, frozen shoulder and sciatica.